1. TACT Trial to Assess Chelation Therapy Principal Investigator Gervasio A. Lamas, MD Mt. Sinai Hospital; Miami Beach, FL

2. TACT Sponsors and Institutional Participants NIH—National Institutes of Health NIH—National Institutes of Health –NCCAM—National Center for Complementary and Alternative Medicine –NHLBI—National Heart, Lung and Blood Institute Other Participating Institutions Other Participating Institutions –Duke Clinical Research Institute (Data Coordinating Center and QOL Data –Brigham and Women’s Hospital (Boston) Clinical Events Committee –Others

3. Basic Features of TACT Study 30 Million Dollar Study 30 Million Dollar Study Study to be conducted at approximately 100 Sites Study to be conducted at approximately 100 Sites Study to be conducted over a 5-year period Study to be conducted over a 5-year period It is a randomized, double-blind, placebo controlled study It is a randomized, double-blind, placebo controlled study Will test the value of chelation therapy and high dose oral vitamins and minerals for coronary artery disease Will test the value of chelation therapy and high dose oral vitamins and minerals for coronary artery disease

4. TACT Rockland County Site Schachter Center for Complementary Medicine 2 Executive Boulevard; Suite 202 Suffern, NY 10901 Phone 845-368-4700; FAX 845-368- 4727 Website: www.schachtercenter.com E-Mail: office@mbschachter.com

5. TACT at the Schachter Center Primary Investigator Primary Investigator –Michael B Schachter MD, CNS, FACAM Clinical Coordinator Clinical Coordinator –Sally Minniefield RN, PAC Assistant Clinical Coordinator Assistant Clinical Coordinator –Dolores Tritico RN

6. Specific Aims To determine whether chelation or high-dose supplements in patients with CHD will reduce the incidence of clinical cardiovascular events; To determine whether chelation or high-dose supplements in patients with CHD will reduce the incidence of clinical cardiovascular events; To determine whether chelation and high-dose supplements have acceptable safety profiles. To determine whether chelation and high-dose supplements have acceptable safety profiles.

7. Why is TACT Being Done? Raging controversy over the value of chelation therapy for treating coronary artery disease Raging controversy over the value of chelation therapy for treating coronary artery disease More than a thousand physicians have used chelation therapy to treat coronary artery disease More than a thousand physicians have used chelation therapy to treat coronary artery disease It has been used for more than 40 years It has been used for more than 40 years Most of these physicians and the patients receiving the treatment think that it is effective Most of these physicians and the patients receiving the treatment think that it is effective However, mainstream medicine regards it as unproven and discourages patients from receiving the treatment However, mainstream medicine regards it as unproven and discourages patients from receiving the treatment

8. NIH Wishes to Settle the Controversy If chelation therapy safe and effective, If chelation therapy safe and effective, –then, many more should receive the treatment –and insurance should cover the treatment If chelation therapy worthless, If chelation therapy worthless, –then, people with coronary artery disease should stop wasting their time and money –and insurance companies should continue to refuse to pay Therefore, a well designed clinical study is necessary Therefore, a well designed clinical study is necessary

9. What is Coronary Artery Disease? Most common form of heart disease Most common form of heart disease Arteries that carry oxygen and nutrients to the heart get blocked with plaque (fatty substances and calcium salts) Arteries that carry oxygen and nutrients to the heart get blocked with plaque (fatty substances and calcium salts) Less oxygen and nutrients reach heart muscle, leading to: Less oxygen and nutrients reach heart muscle, leading to: –Angina Pectoris-Pain in the chest –Heart Attack or Myocardial Infarction

10. How Important is Coronary Artery Disease (CAD)? Most frequent cause of death and morbidity in the United States Most frequent cause of death and morbidity in the United States 7 million Americans suffer from CAD 7 million Americans suffer from CAD More than 500,000 Americans die from CAD each year More than 500,000 Americans die from CAD each year

11. What are Risk Factors for Coronary Artery Disease? High blood pressure High blood pressure High cholesterol levels-Especially high LDL and low HDL High cholesterol levels-Especially high LDL and low HDL Smoking Smoking Obesity Obesity Physical inactivity Physical inactivity Diabetes Diabetes Family history of CAD Family history of CAD Gender-Increased in men compared to premenopausal women of comparable age Gender-Increased in men compared to premenopausal women of comparable age Age-Risk increases with age Age-Risk increases with age

12. How is Coronary Artery Disease (CAD) Diagnosed? Symptoms-e.g chest pain on exertion, shortness of breath Symptoms-e.g chest pain on exertion, shortness of breath Blood tests that help to determine if a heart attack has occurred Blood tests that help to determine if a heart attack has occurred Electrocardiogram (may do with stress test) Electrocardiogram (may do with stress test) Echocardiogram Echocardiogram Imaging studies (e.g thallium scans and angiograms) Imaging studies (e.g thallium scans and angiograms)

13. How is Coronary Artery Disease Treated in the United States? Conventional treatment includes: Conventional treatment includes: –Lifestyle modification (dietary changes and exercise) –Medication (ASA, Beta Blockers, ACE Inhibitors, etc) –Invasive interventions (Bypass, Balloon angioplasty, Stents Despite these “proven” treatments, a national survey reveals that 1/3 of patients seek alternative therapies, including EDTA chelation therapy Despite these “proven” treatments, a national survey reveals that 1/3 of patients seek alternative therapies, including EDTA chelation therapy

14. What is Chelation? Greek word chelos meaning claw Greek word chelos meaning claw Refers to an organic molecule binding a mineral tightly Refers to an organic molecule binding a mineral tightly Examples: chlorophyll is a chelate of magnesium and hemoglobin is a chelate of iron Examples: chlorophyll is a chelate of magnesium and hemoglobin is a chelate of iron EDTA is a synthetic amino acid capable of binding to lead, cadmium and other toxic metals, as well as calcium EDTA is a synthetic amino acid capable of binding to lead, cadmium and other toxic metals, as well as calcium

15. Chelating Agents and Chelation Therapy Many chelating agents Many chelating agents EDTA is a chelating agent approved by the FDA to remove lead from the body EDTA is a chelating agent approved by the FDA to remove lead from the body Chelation therapy involves administering a chelating agent for the purpose of removing a toxic mineral from the body Chelation therapy involves administering a chelating agent for the purpose of removing a toxic mineral from the body Removal of toxic minerals may help coronary artery disease because there is evidence that toxic minerals may play a role in coronary artery disease Removal of toxic minerals may help coronary artery disease because there is evidence that toxic minerals may play a role in coronary artery disease

16. Brief History of EDTA Chelation Therapy 1950’s-EDTA found to be useful to treat lead poisoning 1950’s-EDTA found to be useful to treat lead poisoning Dr. Clark in the 1950’s reasoned that since EDTA is also capable of binding calcium and calcium is found in the clogged arteries in the plaque, perhaps EDTA could be used to treat coronary artery disease Dr. Clark in the 1950’s reasoned that since EDTA is also capable of binding calcium and calcium is found in the clogged arteries in the plaque, perhaps EDTA could be used to treat coronary artery disease Initial clinical observations were very promising and several papers were published supporting its use Initial clinical observations were very promising and several papers were published supporting its use Three small randomized placebo controlled studies in recent years failed to show benefits Three small randomized placebo controlled studies in recent years failed to show benefits Controversy rages over whether or not it is beneficial Controversy rages over whether or not it is beneficial

17. Technique for EDTA Chelation Therapy for CAD Disodium EDTA is a synthetic amino acid Disodium EDTA is a synthetic amino acid Chelates or binds heavy metals and calcium Chelates or binds heavy metals and calcium Intravenous infusion given for 3 hours Intravenous infusion given for 3 hours Administered in MD’s office once a week, usually for 30 to 50 treatments Administered in MD’s office once a week, usually for 30 to 50 treatments Magnesium, potassium, vitamins B6, C, heparin and other components added to infusion Magnesium, potassium, vitamins B6, C, heparin and other components added to infusion

18. EDTA Chelation Therapy for CAD is Part of Full Program Part of a total program that involves diet, supplements, exercise, stress management and medication Part of a total program that involves diet, supplements, exercise, stress management and medication Depletes trace minerals, so these must be replaced with good diet, oral & IV minerals Depletes trace minerals, so these must be replaced with good diet, oral & IV minerals Side effects minimal when the ACAM protocol is followed Side effects minimal when the ACAM protocol is followed

19. Proposed Mechanisms for How Chelation Therapy Works Reduces free radicals Reduces free radicals Removes toxic minerals, such as lead and cadmium, which may contribute to CAD Removes toxic minerals, such as lead and cadmium, which may contribute to CAD Removes soft tissue calcium Removes soft tissue calcium Others Others

20. Possible Side Effects of Properly Given EDTA Chelation Therapy Generally side effects are few and not serious Generally side effects are few and not serious Most common is irritation at the site of infusion Most common is irritation at the site of infusion Rare side effects can include: Rare side effects can include: –Fever –Low blood pressure –Low serum –Headache –Nausea and vomiting –Injury to the kidneys –Others, but extremely

21. Examples of Published Studies Claiming Benefits Danish study Danish study Brazilian study Brazilian study Meta-analysis Meta-analysis Review article by Dr. Schachter Review article by Dr. Schachter

22. Reducing CV Surgical Intervention With Mg-EDTA Retrospective Danish study involving 470 CV patients involving many parameters Retrospective Danish study involving 470 CV patients involving many parameters 80—91% improved from baseline depending on parameter used 80—91% improved from baseline depending on parameter used Waiting list for CABG or amputation Waiting list for CABG or amputation 58/65 did not need CABG after chelation 58/65 did not need CABG after chelation 24/27 did not need amputation after chelation 24/27 did not need amputation after chelation Hancke C & Flytlie K. Journal of Advancement in Medicine, Vol. 6, Number 3, Fall 1993, 161-171.

23. EDTA For Heart, Peripheral and Brain Circulation Brazilian retrospective study involving 2,870 patients with CV and other diseases Brazilian retrospective study involving 2,870 patients with CV and other diseases Objective criteria used Objective criteria used 98% peripheral CV showed marked or good 98% peripheral CV showed marked or good 93% coronary CV showed marked or good 93% coronary CV showed marked or good 60% cerebro CV showed marked or good 60% cerebro CV showed marked or good Olszewer, E & Carter JP. Medical Hypothesis, 27, 1988, 41-49.

24. Meta-analysis Of EDTA Chelation For CV Disease Review of 19/40 articles involving 22,765 patients that met criteria to measure effects of EDTA on CV disease Review of 19/40 articles involving 22,765 patients that met criteria to measure effects of EDTA on CV disease Correlation coefficient of 0.88 suggesting a high positive relationship between EDTA therapy and improved CV function Correlation coefficient of 0.88 suggesting a high positive relationship between EDTA therapy and improved CV function 87% of patients improved 87% of patients improved Chappell LT & Stahl JP. Journal of Advancement in Medicine, Vol.6, No.3, Fall 1993, 139-159.

25. Review Article on EDTA Chelation Therapy “Overview, historical background and current status of EDTA chelation therapy for atherosclerosis” “Overview, historical background and current status of EDTA chelation therapy for atherosclerosis” Reviews of scientific studies, clinical reports Reviews of scientific studies, clinical reports Analysis of controversies Analysis of controversies Schachter MB, Journal of Advancement in Medicine, Vol.9, No.3, Fall 1996, 159-177.

26. Criticism of Positive Articles on Chelation Therapy Published in journal of organization that promotes EDTA chelation therapy and teaches it to physicians Published in journal of organization that promotes EDTA chelation therapy and teaches it to physicians All authors are strong proponents of chelation therapy and may be biased All authors are strong proponents of chelation therapy and may be biased Studies not randomized, double-blind or placebo controlled Studies not randomized, double-blind or placebo controlled For these and other reasons, most conventional clinicians are skeptical and think the treatment is at best unproven For these and other reasons, most conventional clinicians are skeptical and think the treatment is at best unproven

27. NCCAM View of EDTA Chelation Therapy Evidence for CAD-1 Bulk of the evidence supporting EDTA chelation therapy is in the form of case reports and case series. Bulk of the evidence supporting EDTA chelation therapy is in the form of case reports and case series. Approximately 12 published descriptive studies and 5 randomized controlled clinical trials regarding the use of EDTA chelation for CAD. Approximately 12 published descriptive studies and 5 randomized controlled clinical trials regarding the use of EDTA chelation for CAD. Although each descriptive study did report a reduction in angina, they were uncontrolled clinical observations or retrospective data, typically with a small number of participants. Although each descriptive study did report a reduction in angina, they were uncontrolled clinical observations or retrospective data, typically with a small number of participants.

28. NCCAM View of EDTA Chelation Therapy Evidence for CAD-2 Of the five clinical trials in which patients were randomly selected to receive chelation therapy or a placebo (a dummy solution), the most rigorous way of assessing a new treatment, three trials involved so few people that only a dramatic improvement could have been detected. Studies need larger number of participants to detect more mild benefits of a treatment. Of the five clinical trials in which patients were randomly selected to receive chelation therapy or a placebo (a dummy solution), the most rigorous way of assessing a new treatment, three trials involved so few people that only a dramatic improvement could have been detected. Studies need larger number of participants to detect more mild benefits of a treatment. The fourth study was never published in final form, so its conclusions are uncertain. The fourth study was never published in final form, so its conclusions are uncertain. Finally, the fifth study reported that EDTA chelation was associated with an improvement in ability to exercise, but it had only 10 participants. Finally, the fifth study reported that EDTA chelation was associated with an improvement in ability to exercise, but it had only 10 participants.

29. TACT’s Attempt to Settle the Question Multicenter study involving as many as 100 sites or more Multicenter study involving as many as 100 sites or more Some sites are run by chelation proponents and others by conventional cardiologists or other conventional MDs, who are skeptical Some sites are run by chelation proponents and others by conventional cardiologists or other conventional MDs, who are skeptical Study is randomized, double-blind and placebo controlled Study is randomized, double-blind and placebo controlled

30. TACT Design 5-year randomized, double-blind, placebo- controlled; 5-year randomized, double-blind, placebo- controlled; 2X2 factorial trial; 2X2 factorial trial; Testing the standard chelation solution versus placebo; Testing the standard chelation solution versus placebo; Testing the effects of a high-dose antioxidant vitamin and mineral supplementation, versus placebo. Testing the effects of a high-dose antioxidant vitamin and mineral supplementation, versus placebo.

31. Specific Aims To determine whether chelation or high-dose supplements in patients with CHD will reduce the incidence of clinical cardiovascular events; To determine whether chelation or high-dose supplements in patients with CHD will reduce the incidence of clinical cardiovascular events; To determine whether chelation and high-dose supplements have acceptable safety profiles. To determine whether chelation and high-dose supplements have acceptable safety profiles.

32. Details of TACT Trial: Factorial Design—Two Trials in One Total number of patients 2,372 Total number of patients 2,372 Half (1,186) get chelation and half get placebo Half (1,186) get chelation and half get placebo Half of each group above (593) will get oral high dose vitamin and mineral supplements (6 pills) and half of each group will get oral placebo that looks like high dose vitamin and mineral Half of each group above (593) will get oral high dose vitamin and mineral supplements (6 pills) and half of each group will get oral placebo that looks like high dose vitamin and mineral All participants will receive a single vitamin- mineral pill containing: B6, Zinc, Manganese, Copper and Chromium All participants will receive a single vitamin- mineral pill containing: B6, Zinc, Manganese, Copper and Chromium

33. Primary Endpoint Composite clinical endpoint including: Composite clinical endpoint including: –all cause mortality –myocardial infarction –stroke –coronary revascularization –hospitalization for angina

34. Secondary Endpoints Composite serious irreversible vascular events including: cardiovascular death, or non-fatal MI or non-fatal stroke. Composite serious irreversible vascular events including: cardiovascular death, or non-fatal MI or non-fatal stroke.

35. Substudy Specific Aims Two substudies will be conducted whose specific aims are as follows: To determine whether chelation or high-dose supplements improve quality of life; To determine whether chelation or high-dose supplements improve quality of life; To conduct an economic analysis of chelation therapy and high dose supplements. To conduct an economic analysis of chelation therapy and high dose supplements.

36. Quality of Life Endpoints Cardiac physical functioning: Duke Activity Status Index Cardiac physical functioning: Duke Activity Status Index Psychological well-being: SF-36 MHI5 Psychological well-being: SF-36 MHI5 Angina symptoms from Seattle Angina Questionnaire Angina symptoms from Seattle Angina Questionnaire Patient utilities: EuroQoL Patient utilities: EuroQoL Analysis by intention to treat Analysis by intention to treat Baseline Questionnaire on every randomized patient administered by the Site Coordinator Follow-up Questionnaire on 1000 randomized subset by DCRI telephone at 6, 12 and 24 months

37. Timeline First patient enrolled September 2003. First patient enrolled September 2003. Enroll for 3 years. Enroll for 3 years. Follow patients until August 2007. Follow patients until August 2007. Trial ends in November 2007. Trial ends in November 2007.

38. Inclusion Criteria Men or women age 50 and older Men or women age 50 and older MI >6 weeks prior to randomization MI >6 weeks prior to randomization T A C T

39. Definition of MI Biomarkers + (symptoms or ECG changes) Biomarkers + (symptoms or ECG changes) OR OR Imaging evidence of myocardial scar + evidence of coronary disease on angiography. Imaging evidence of myocardial scar + evidence of coronary disease on angiography. This requires PI involvement, especially the decision that the CAD corresponds to an imaged scar. Remember that the CCC is always happy to help.

40. Major Exclusion Criteria-1 Chelation within 5 years Chelation within 5 years Known allergy to any components of solutions or vitamins (heparin may be omitted from the infusion) Known allergy to any components of solutions or vitamins (heparin may be omitted from the infusion) Carotid or coronary revascularization within 6 months, or planned revascularization Carotid or coronary revascularization within 6 months, or planned revascularization Symptomatic HF, or HF hospitalization within 6 months Symptomatic HF, or HF hospitalization within 6 months

41. Major Exclusion Criteria-2 Uncontrolled hypertension (BP>160/100) Uncontrolled hypertension (BP>160/100) No venous access No venous access Creatinine >2.0mg/dL Creatinine >2.0mg/dL Baseline platelets <100,000 Baseline platelets <100,000 Cigarette smoking within 3 months Cigarette smoking within 3 months

42. Study Interventions ACAM protocol EDTA chelation vs placebo ACAM protocol EDTA chelation vs placebo High dose antioxidant vitamins and minerals vs placebo High dose antioxidant vitamins and minerals vs placebo

43. Additive Role of Additive Up to 3 grams of disodium EDTA 2 grams of magnesium chloride To reduce local discomfort and replace losses 100 mg of procaine HCL To reduce local discomfort 2500 units of heparin To reduce local phlebitis 7 grams of ascorbate Anti-oxidant and to achieve isoosmolarity 2 mEq KCl To replace losses 840 mg sodium bicarbonate To act as a buffer and reduce discomfort 250mg pantothenic acid For anti-oxidant properties 100mg of thiamine For anti-oxidant properties 100mg of pyridoxine QS with sterile water to 500ml To replace chelation losses Chelation Solution Chelation placebo solution is 500 ml 500cc of 0.9N NaCl, and 1.2% dextrose

44. Pharmacy – Delivery of Study Drugs Infusion Kits – UPS delivery the morning before scheduled visit Infusion Kits – UPS delivery the morning before scheduled visit – 500 ml bag IV solution – 2 - 20ml syringes Vitamins – Initial supply shipped with first kit Vitamins – Initial supply shipped with first kit –Subsequent shipments every two months –Subsequent shipments contain 2-month supply (360 tablets in a bottle; 60 gel-caps in blister packs) –After the completion of the 40 th infusion, shipments will be done on a quarterly basis.

45. Pharmacy – Simple Mixing Instructions Prepare infusion just prior to administration Prepare infusion just prior to administration Inject 2 syringes of solution into IV bag using 21 g needles Inject 2 syringes of solution into IV bag using 21 g needles Allow solution to reach room temp prior to infusing (30 minutes) Allow solution to reach room temp prior to infusing (30 minutes) Administer within 24 hrs of mixing Administer within 24 hrs of mixing

46. Drug Shipment

47. Blinding the Therapy

48. Non-Study Interventions Up to date guidelines for medical management of post-MI patients including statins, aspirin, beta-blockers, and ACE inhibitors. Up to date guidelines for medical management of post-MI patients including statins, aspirin, beta-blockers, and ACE inhibitors.

49. Study Overview Screening and Randomization Screening and Randomization –Perform initial screening –Obtain informed consent –Submit lab samples –Complete screening worksheet –Administer EQOL Baseline Questionnaire –Review lab results for eligibility –Randomize via TrialMaster

50. Study Overview Infusion Visits Infusion Visits –Initial - Weekly X 30 wks –Maintenance - Every 2 – 8 weeks –Enter data into TM during or immediately post visit

51. Study Overview Patient Follow-up: Patient Follow-up: –3 phone calls/year (average 2.5 years f/u) –1 annual clinic visit –Clinic visit at end of study

52. Why Should You Enroll in TACT? Why Should You Enroll in TACT? No cost to anyone participating in the study (the cost for the treatment for those receiving the active treatment would probably be somewhere between $5,000 and $8,000) No cost to anyone participating in the study (the cost for the treatment for those receiving the active treatment would probably be somewhere between $5,000 and $8,000) Potential benefit if EDTA chelation beneficial Potential benefit if EDTA chelation beneficial Potential benefit if high dose vitamins and minerals are beneficial Potential benefit if high dose vitamins and minerals are beneficial Everyone gets low dose nutrient pill Everyone gets low dose nutrient pill 75% chance of getting chelation, high dose vitamin mineral or both 75% chance of getting chelation, high dose vitamin mineral or both Altruistic-Contribute to knowledge about benefits of EDTA chelation therapy Altruistic-Contribute to knowledge about benefits of EDTA chelation therapy In general, subjects in a study are watched closely and generally do better than patients not in a study In general, subjects in a study are watched closely and generally do better than patients not in a study